Immunity can generally be classified as innate immunity or as adaptive immunity. Innate immune responses typically occur immediately upon infection to provide an early barrier to infectious disease whereas adaptive immune responses occur later with the generation of antigen-specific effector cells and often long term protective immunity. Innate immune responses do not generate lasting protective immunity but appear to play a role in the generation of the later arising adaptive immune response.
Innate immunity uses germ-line encoded receptors to recognize features that are common to many pathogens and to activate signalling events that result in the expression of effector molecules. Some of these effector molecules may eventually induce an adaptive immune response. The family of Toll-like receptors (TLRs) have been associated with innate immune response signalling and microbial ligands have been identified for several mammalian TLRs. For example, TLR2 interacts with peptidoglycan, bacterial lipopeptides and certain types of lipopolysaccharide (LPS), TLR3 interacts with double-stranded RNA, TLR4 interacts with LPS and TLR-5 interacts with bacterial flagellin. See, for example, Poltorak et al. (1998) Science 282:2085-2088; Akira et al. (2003) Immunol. Lett. 85:85-95; Alexopoulou et al. (2001) Nature 413:732-738; Hayashi et al. (2001) Nature 410:1099-1103. TLR-7 is activated by guanosine analogs, by small antiviral compounds such as imidazoquinolines, imiquimod and R-848, and by single-stranded viral RNA and TLR-8 is also activated by R-848 and single-stranded viral RNA. See, for example, Lee et al. (2003) Proc. Natl. Acad. Sci. USA 100:6646-6651; Hemmi et al. (2002) Nat. Immunol. 3:196-200; Jurk et al. (2002) Nat. Immunol. 3:499; Heil et al. (2004) Science 303:1526-1529; Diebold et al. (2004) Science 303:1529-1531. TLR-9 has been shown to recognize immunostimulatory nucleic acid molecules such as bacterial DNA and immunostimulatory DNA containing a 5′-CG-3′ sequence. See, for example, Hemmi et al. (2000) Nature 408:740-745; Bauer et al. (2001) Proc. Natl. Acad. Sci. USA 98:9237-9242; Takeshita et al. (2001) J. Immunol. 167:3555-3558. In addition, certain TLRs (for example, TLR-1, TLR-2 and TLR-6) can heterodimerize, interact with their microbial ligands and lead to cell activation, thus expanding the ligand repetoire of the TLR family. Ozinsky et al. (2000) J. Endotoxin Res. 6:393-396; Ozinsky et al. (2000) Proc. Natl. Acad. Sci. USA 97:13766-13771.
Immunostimulatory nucleic acid (ISNA) molecules, such as bacterial DNA or a polynucleotide containing unmethylated 5′-CG-3′ sequences, can stimulate innate immune responses, such as cytokine production, and dendritic cell and macrophage activation, and then lead to a Th1-type immune response. Immunostimulatory nucleic acid molecules stimulate the immune response through interaction with and signalling through the mammalian TLR9 receptor. Hemmi et al. (2000), Supra. Mammalian DNA does not generally possess immunostimulatory activity due apparently to a low frequency of CG sequences and to most of the CG sequences having a methylated cytosine. Mammalian immune system cells thus appear to distinguish bacterial DNA from self DNA through the TLR9 receptor.
Immunostimulatory nucleic acid molecules have been implicated in the pathogenesis of arthritis. Immunostimulatory nucleic acid has been shown to play a role in activation of autoreactive B cells such as those produce a class of autoantibodies known as rheumatoid factor (RF). Thus, such immunostimulatory nucleic acids appear to play a role in systemic autoimmunity. In addition, immunostimulatory nucleic acid can enhance toxicity of LPS and contribute to adverse effects of administration of vectors for gene therapy. See, for example, Deng et al. (1999) Nature Med. 5:702-705, Leadbetter et al. (2002) Nature 416:603-607, Cowdery et al. (1996) J. Immunol. 156:4570-4575, U.S. Pat. No. 6,225,292.
There remains a need to identify strategies to control unwanted immune activation, including unwanted activation of the innate immune response.
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